Research progress on application of multi-enzyme-catalyzed cascade reactions in enzymatic synthesis of natural products / 中国中药杂志

As a biocatalyst, enzyme has the advantages of high catalytic efficiency, strong reaction selectivity, specific target products, mild reaction conditions, and environmental friendliness, and serves as an important tool for the synthesis of complex organic molecules. With the continuous development of gene sequencing technology, molecular biology, genetic manipulation, and other technologies, the diversity of enzymes increases steadily and the reactions that can be catalyzed are also gradually diversified. In the process of enzyme-catalyzed synthesis, the majority of common enzymatic reactions can be achieved by single enzyme catalysis, while many complex reactions often require the participation of two or more enzymes. Therefore, the combination of multiple enzymes together to construct the multi-enzyme cascade reactions has become a research hotspot in the field of biochemistry. Nowadays, the biosynthetic pathways of more natural products with complex structures have been clarified, and secondary metabolic enzymes with novel catalytic activities have been identified, discovered, and combined in enzymatic synthesis of natural/unnatural molecules with diverse structures. This study summarized a series of examples of multi-enzyme-catalyzed cascades and highlighted the application of cascade catalysis methods in the synthesis of carbohydrates, nucleosides, flavonoids, terpenes, alkaloids, and chiral molecules. Furthermore, the existing problems and solutions of multi-enzyme-catalyzed cascade method were discussed, and the future development direction was prospected.

Synthetic biology for the synthesis of mogroside V - a review / 生物工程学报

Mogroside V, a component with high content and sweetness in mogrosides, has many pharmacological activities such as relieving cough, reducing sputum, anti-cancer, anti-oxidation, regulating blood sugar, making it a natural nonsugar sweetener with therapeutic functions, and showing a broad market prospect. However, the limited resources and high extraction costs have restricted its widespread use. The rapid development of synthetic biology has provided a new idea for the production of plant natural products. The low-cost and large-scale production will be realized through the construction of a microbial cell factory for mogroside V. Here, we briefly introduce the structure and pharmacological activity of mogroside V, and review progress in applying synthetic biology for its synthesis, and also discuss the challenges faced by the current research, to provide a reference for further studies on the biosynthesis of mogroside V.

Natural products as new antimitotic compounds for anticancer drug development

Cell cycle control genes are frequently mutated in cancer cells, which usually display higher rates of proliferation than normal cells. Dysregulated mitosis leads to genomic instability, which contributes to tumor progression and aggressiveness. Many drugs that disrupt mitosis have been studied because they induce cell cycle arrest and tumor cell death. These antitumor compounds are referred to as antimitotics. Vinca alkaloids and taxanes are natural products that target microtubules and inhibit mitosis, and their derivatives are among the most commonly used drugs in cancer therapy worldwide. However, severe adverse effects such as neuropathies are frequently observed during treatment with microtubule-targeting agents. Many efforts have been directed at developing improved antimitotics with increased specificity and decreased likelihood of inducing side effects. These new drugs generally target specific components of mitotic regulation that are mainly or exclusively expressed during cell division, such as kinases, motor proteins and multiprotein complexes. Such small molecules are now in preclinical studies and clinical trials, and many are products or derivatives from natural sources. In this review, we focused on the most promising targets for the development of antimitotics and discussed the advantages and disadvantages of these targets. We also highlighted the novel natural antimitotic agents under investigation by our research group, including combretastatins, withanolides and pterocarpans, which show the potential to circumvent the main issues in antimitotic therapy.

Natural antifouling compound production by microbes associated with marine macroorganisms: A review

In the marine environment, all hard surfaces including marine macroorganims are colonized by microorganisms mainly from the surrounding environment. The microorganisms associated with marine macroorganisms offer tremendous potential for exploitation of bioactive metabolites. Biofouling is a continuous problem in marine sectors which needs huge economy for control and cleaning processes. Biotechnological way for searching natural product antifouling compounds gained momentum in recent years because of the environmental pollution associated with the use of toxic chemicals to control biofouling. While, natural product based antifoulants from marine organisms particularly sponges and corals attained significance due to their activities in field assays, collection of larger amount of organisms from the sea is not a viable one. The microorganisms associated with sponges, corals, ascidians, seaweeds and seagrasses showed strong antimicrobial and also antifouling activities. This review highlights the advances in natural product antifoulants research from microbes associated with marine organisms.

Cell cross-talk and interactions: a review of structure and function

Cell-cell interactions are central to the function of many organ systems. The contact between cells and their microenvironment is fundamental both during development and for the preservation of tissue structure. Picking out the signals coming from the surrounding environment enables cells to react promptly to changes that may occur. This work provides a comprehensive review on cell interactions and cross-talk in normal physiological and some pathological conditions of different tissues and organs of the human body [e.g. embryonic, vascular, dendritic, natural killer, cardiac, nerve, lung, testicular, epidermal, and dermal cells]. It aimed to explore the nature of this phenomenon and its role in regulating or directing normal cellular function. The mode of cellular interaction was discussed on the basis of biochemical data regarding cytokines or through actual cell contact through different types of junctions or synaptic ribbons. Further understanding of how cell-cell interactions modulate tissue function will allow us to gain fundamental biological insight as well as suggest approaches that will allow the manipulation of tissue function in vitro and for therapeutic applications in vivo

Investigación en Química de Productos Naturales en Argentina: Vinculación con la Bioquímica / Development and Research Trends in Chemistry of Natural Products in Argentina: Connection with Biochemistry and Clinical Biochemistry / Pesquisa em Química de Produtos Naturais na Argentina: Vinculagáo com a Bioquímica

En este trabajo se detallan las características y objetivos de la especialidad de Química de Productos Naturales, analizando los conocimientos requeridos de otras especialidades para realizar investigación en la misma. A través de un breve desarrollo histórico se puede observar la vinculación con varias ramas de la Química, como Química Orgánica, Química Biológica y Química Bioanalítica, así como Bioquímica Clínica, entre otras. Se brindan las perspectivas de esta especialidad, mostrando las tendencias en la investigación y en la industria química internacional. El trabajo multidisciplinario se evidencia en las aplicaciones presentadas en investigación.

This article is focused on the characteristics and aims of the Chemistry of Natural Products analyzing the required knowledge from other fields to carry out research. Through a brief historical development, it can be observed that it is related with various branches of Chemistry, including Organic Chemistry, Biological Chemistry and Bioanalytical Chemistry as well as Clinical Biochemistry, among others. Prospects in this field are provided, showing trends in research and in the international chemical industry. A multidisciplinar approach is evident in the research projects shown herein.

Neste trabalho sáo detalhadas as características e objetivos da especialidade de Química de Produtos Naturais, analisando os conhecimentos requeridos de outras especialidades para realizar pesquisa na mesma. Através de um breve desenvolvimento histórico é possível observar a vinculagáo com vários ramos da Química, como Química Orgánica, Química Biológica e Química Bioanalítica, bem como Bioquímica Clínica, dentre outras. Sáo oferecidas as perspectivas desta especialidade, mostrando as tendencias na pesquisa e na indústria química internacional. O trabalho multidisciplinar se evidencia nas aplicagóes apresentadas em pesquisa.

The potential of secondary metabolites from plants as drugs or leads against protozoan neglected diseases - part I

Infections with protozoan parasites are a major cause of disease and mortality in many tropical countries of the world. Diseases caused by species of the genera Trypanosoma (Human African Trypanosomiasis and Chagas Disease) and Leishmania (various forms of Leishmaniasis) are among the seventeen "Neglected Tropical Diseases" (NTDs) defined as such by WHO due to the neglect of financial investment into research and development of new drugs by a large part of pharmaceutical industry and neglect of public awareness in high income countries. Another major tropical protozoan disease is malaria (caused by various Plasmodium species), which -although not mentioned currently by the WHO as a neglected disease- still represents a major problem, especially to people living under poor circumstances in tropical countries. Malaria causes by far the highest number of deaths of all protozoan infections and is often (as in this review) included in the NTDs. The mentioned diseases threaten many millions of lives world-wide and they are mostly associated with poor socioeconomic and hygienic environment. Existing therapies suffer from various shortcomings, namely, a high degree of toxicity and unwanted effects, lack of availability and/or problematic application under the life conditions of affected populations. Development of new, safe and affordable drugs is therefore an urgent need. Nature has provided an innumerable number of drugs for the treatment of many serious diseases. Among the natural sources for new bioactive chemicals, plants are still predominant. Their secondary metabolism yields an immeasurable wealth of chemical structures which has been and will continue to be a source of new drugs, directly in their native form and after optimization by synthetic medicinal chemistry. The current review, published in two parts, attempts to give an overview on the potential of such plant-derived natural products as antiprotozoal leads and/or drugs in the fight against NTDs.

In vitro anticancer activity of microbial isolates from diverse habitats / In vitro atividade anticancerígena de isolados microbianos de diversos habitats

Extracts from natural products, especially microorganisms, have served as a valuable source of diverse molecules in many drug discovery efforts and led to the discovery of several important drugs. Identification of microbial strains having promising biological activities and purifying the bio-molecules responsible for the activities, have led to the discovery of many bioactive molecules. Extracellular, as well as intracellular, extracts of the metabolites of thirty-six bacterial and twenty-four fungal isolates, grown under unusual conditions such as high temperature, high salt and low sugar concentrations, were in vitro tested for their cytotoxic potential on various cancer cell lines. The extracts were screened on HeLa and MCF-7 cell lines to study the cytotoxic potential. Nuclear staining and flow cytometric studies were carried out to assess the potential of the extracts in arresting the cell cycle. The crude ethylacetate extract of isolate F-21 showed promising results by MTT assay with IC50 as low as 20.37±0.36 µg/mL on HeLa, and 44.75±0.81 µg/mL on MCF-7 cells, comparable with Cisplatin. The isolate F-21 was identified as Aspergillus sp. Promising results were also obtained with B-2C and B-4E strains. Morphological studies, biochemical tests and preliminary chemical investigation of the extracts were also carried out.

Extratos de produtos naturais, especialmente de microrganismos, constituíram-se em fonte valiosa de diversas moléculas em muitas descobertas de fármacos e levaram à descoberta de fármacos importantes. A identificação de espécies microbianas que apresentam atividade biológica e a purificação de biomoléculas responsáveis pelas atividades levou à descoberta de muitas moléculas bioativas. Extratos extracelulares tanto quanto intracelulares de metabólitos de 36 isolados de bactérias e 24 isolados de fungos, que cresceram sob condições não usuais, como alta temperatura, alta concentração de sal e baixa concentração de açúcar, foram testados in vitro quanto ao seu potencial citotóxico em várias linhagens de câncer. Os extratos foram ensaiados em células HeLa e MCF-7 para o estudo do potencial citotóxico. A coloração nuclear e os estudos de citometria de fluxo foram realizados para avaliar o potencial dos extratos em bloquear o ciclo celular. O extrato bruto em acetato de etila do isolado F-21 mostrou resultados promissores no ensaio de MTT, com IC50 de 20,37±0,36 µg/mL em células HeLa e 44,.75±0,81 µg/mL em células MCF-7, comparativamente à cisplatina. O isolado F-21 foi identificado como Aspergillus sp. Resultados promissores foram obtidos com cepas B-2C e B-4E. Realizaram-se, também, estudos morfológicos, testes bioquímicos e investigação química preliminar dos extratos.

A moderna química de produtos naturais no Brasil: as origens do Núcleo de Pesquisas de Produtos Naturais da UFRJ / The modern chemistry of natural products in Brazil: the origins of the Núcleo de Pesquisas de Produtos Naturais da UFRJ

Os depoimentos apresentam a história do Núcleo de Pesquisas de Produtos Naturais da Universidade Federal do Rio de Janeiro, criado em 1963 após a extinção do Instituto de Química Agrícola, do Ministério da Agricultura. Decorridos quase cinqüenta anos, dois dos remanescentes do antigo instituto contam as suas versões desta história.

The testimonies disclose the history of the Núcleo de Pesquisas de Produtos Naturais da Universidade Federal do Rio de Janeiro, created in 1963, after the closure of the Instituto de Química Agrícola (Agricultural Chemistry Institute), Ministry of Agriculture. Almost 50 years.

Psammaplin A is a natural prodrug that inhibits class I histone deacetylase

Histone deacetylase (HDAC) has been highlighted as one of key players in tumorigenesis and angiogenesis. Recently, several derivatives of psammaplin (Psams) from a marine sponge have been known to inhibit the HDAC activity, but the molecular mechanism for the inhibition has not fully understood. Here, we explored the mode of action of Psams for the inhibition of HDAC activity in the molecular and cellular level. Among the derivatives, psammaplin A (Psam A) showed the potent inhibitory activity in enzyme assay and anti-proliferation assay with IC50 value of 0.003 and 1 microM, respectively. Psam A selectively induced hyperacetylation of histones in the cells, resulting in the upregulation of gelsolin, a well-known HDAC target gene, in a transcriptional level. In addition, reduced Psam A showed a stronger inhibitory activity than that of non-reduced one. Notably, glutathione-depleted cells were not sensitive to Psam A, implying that cellular reduction of the compound is responsible for the HDAC inhibition of Psam A after uptake into the cells. Together, these data demonstrate that Psam A could exhibit its activity under the reduced condition in the cells and be a new natural prodrug targeting HDAC.

A study on antigenic and allergenic changes during storage in three different biological extracts.

The stability of three allergens common in tropical countries was evaluated under different storage conditions. Prosopis juliflora (PJ), Rhizopus nigricans (RN), and wheat dust (WD), were taken as representatives of various groups of allergens viz, pollen, fungi and dust. The extracts were stored in buffer containing phenol (0.4%) or glycerol (50%) at temperatures ranging from 4-55 degrees C for 15 to 60 days. Protein content of PJ extract was reduced remarkably when it was stored at 40 degrees C for 45 days. Thin layer isoelectric focusing and rocket immunoelectrophoresis of PJ showed that certain antigenic proteins degrade rapidly even at 25 degrees C as early as day 15. However, two to three proteins of PJ remain stable at a higher temperature (40 degrees C) for two months. Relative radioallergosorbent test (RAST) inhibition showed substantial loss of allergenic activity in all the three extracts, when stored at higher temperatures (25-55 degrees C) even for short durations, i.e., 15 days. Extracts (PJ and RN) containing 50% glycerol were found to be stable, retaining more than 50% activity, even when stored at 55 degrees C for 40 days, while extracts without glycerol lost more than 75% of their allergenic activity. However, addition of glycerol did not change the stability of wheat dust allergenic extract. The present findings indicate that allergenic extracts behave differently when stored. Hence, the stability of each extract should be determined individually.

Potential sources of biodynamically active natural products in Brazil

In contrast to China where vegatation is predominantly herbaceous, vegetation in Brazil is commonly arboreous. This fact may explain why Chinese drugs are usually acetate derived, while actual and potential natural therapeutic agents from Brazil are mostly shikimate derived. Only relatively few compounds isolated from Brazilian plants have been submitted to adequate pharmacological testing .